Low-temperature inhalation administration of cannabinoid entities

ABSTRACT

A cannabinoid material as active agent containing formulation comprising the active agent, an HFA propellant, and optionally a co-solvent is disclosed. Also disclosed is an inhalation method of administration of the formulation without the use of heat greater than 50° C.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 15/634,249, filed2017 Jun. 17, pending; which is a continuation of U.S. Ser. No.15/196,315, filed 2016 Jun. 29, now issued as U.S. Pat. No. 9,717,683 on2017 Aug. 01.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

FIELD OF THE INVENTION

The present invention is directed to the field of cannabinoid plantextracts and cannabinoid active agents, especially to cannabidiol (CBD),cannabidiolic acid (CBD Acid), tetrahydrocannabinol (THC),tetrahydrocannabinolic acid (THC Acid), tetrahydrocannabivarin (THCV),tetrahydrocannabivarinic acid (THCV Acid), cannabinol (CBN),cannabinolic acid (CBN Acid), cannabigerol, and cannabigerolic acid asactive agents. The invention also relates to the field of formulationsof these materials for inhalation therapy, as well as to the field ofinhalation therapeutic therapies.

BACKGROUND OF THE INVENTION

The field of therapeutic use of cannabinoid active agents has blossomedin recent decades as the therapeutic use of cannabinoids has becomelegalized in more and more jurisdictions. Most uses of cannabinoids,whether as whole plant, extracts of the plants, and as purifiedcompounds (natural or synthetic), has been primarily in the direction of(a) ingesting the materials orally either as solid oral dosage forms orby means of being baked into various orally ingestible baked goods, (b)delivery to the lungs by virtue of (1) smoking cannabinoid containingplant parts, or (2) vaporizing extracts (partially or highly purifiedcompounds)—whether solid or liquid—via the application of heat in orderto vaporize the cannabinoid containing substance. While these methods ofadministration do deliver active principles, each of these methodssuffer from various defects and problems. For example, one problem isthe fact that the application of heat to cannabinoids changes thecomposition of the plant cannabinoids in significant part from forexample cannabinoid acids to corresponding non-acid cannabinoids. In thecase of THC (tetrahydrocannabinol), the structurally different acidversion of the material (tetrahydrocannabinolic acid) is substantiallyless psychotropic than the tetrahydrocannabinol itself. Thus,application of heat, either during the process of extraction or in thecourse of delivery by smoking the material or in the use of vaporizers,increases the psychoactive effects. In the case of CBD (cannabidiol) andthe acid forms of the other cannabinoids, which are not psychotropic,the structurally different acid version of the material (cannabidiolicacid et cetera) has shown increased in vivo activity compared to thecannabidiol itself and the corresponding non-acid forms of the othercannabinoids, respectively. Thus, the application of heat, either duringthe process of extraction or in the course of smoking the material or inthe use of vaporizers, modifies the in-vivo effects. In both cases, theacid form of the material is the precursor of the correspondingdecarboxylated material. As the therapeutic uses of cannabinoids aredirected to activities other than the psychoactive effects, the use ofsmoking and vaporizing as delivery methods are disadvantageous. Inaddition, oral ingestion modes of administration, including sublingualadministration, require significant doses in order to obtain the desiredeffects due to a very high first pass metabolism effect of cannabinoids.Thus, administration methods that can avoid the first pass metabolismeffect would be desirable as allowing for reduction in dosage amountsneeded to obtain desired effects.

OBJECTS OF THE INVENTION

It is among the objects of the present invention to provide aformulation of cannabinoid active principles that can avoid the firstpass metabolism effects associated with oral delivery or ingestion,including sublingual delivery.

It is another object of the invention to provide a formulation ofextracts of cannabinoid containing plant parts, the extracts containingcannabinoid active principles that can be administered in suitable doseswithout the use of heating above 50° C.

It is another object of the invention to provide a formulation ofsynthetic or semi-synthetic cannabinoids that can be administered insuitable doses without the use of heating above 50° C.

It is yet another object of the invention to provide an extractionprocedure of cannabinoid material containing plant parts, in which theextracts are obtained without the use of heating above 50° C.

It is still another object of the invention to provide an inhalationsuitable formulation of one or more cannabinoid active principles.

It is still another object of the invention to provide an inhalationsuitable formulation of one or more cannabinoid active principlescapable of being delivered to a subject in microdoses.

Yet a further object of the invention is to provide an inhalationsuitable formulation of one or more extracts of a cannabinoid containingplant.

Still a further object of the invention is to provide an inhalationsuitable formulation of one or more cannabinoid containing activeprinciples where such formulation has as a principle solvent, apharmaceutically acceptable propellant, with or without apharmaceutically and inhalation suitable co-solvent.

An even further object of the invention is to provide a metered doseinhalation suitable formulation containing one or more cannabinoidactive principles.

Yet an even further object of the invention is to provide a metered doseinhaler system for delivery of the foregoing cannabinoid containingformulations of the previous object of the invention.

Still an even further object of the invention is to provide a method oftreatment of a cannabinoid active principle responsive condition viaadministration of an inhalation suitable formulation of the cannabinoidactive principle without the use of the application of heat over 50° C.and without the use of burning.

Yet another object of the invention is to provide a metered dose inhalerthat delivers one or more formulations of the previous objects of theinvention in therapeutically effective amounts for one or more of thevarious cannabinoid responsive conditions, which therapeuticallyeffective amount is substantially reduced relative to the dose neededfor oral or sublingual administration thereof.

Still another object of the invention is to provide a method oftreatment of a cannabinoid responsive condition with substantiallyreduced psychoactive effects relative to administration by smoking or byvaporizing and at a substantially reduced therapeutically active dosageas compared to oral administration, sublingual administration, ortopical administrations.

Still other objects of the invention will be recognized by those ofordinary skill in the art.

BRIEF SUMMARY OF THE INVENTION

These and other objects of the invention are surprisingly achieved by aformulation of (1) a cannabinoid material selected from the groupconsisting of (a) an extract of a cannabinoid containing plant part, (b)a cannabinoid active principle in partially or completely purified form,(c) a synthetic cannabinoid, or (d) a combination thereof; dissolved inone or more pharmaceutically and inhalation acceptable propellant(s),optionally in the presence of one or more pharmaceutically andinhalation acceptable co-solvent(s) for the cannabinoid material(s);which formulation is delivered via a metered dose inhaler device withoutthe need for heating over 50° C. during delivery.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a partial cross-sectional view of a metered dose inhalergenerally known in the art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a formulation of (1) a cannabinoid materialselected from the group consisting of (a) an extract of a cannabinoidcontaining plant part, (b) a cannabinoid active principle in partiallyor completely purified form, (c) a synthetic cannabinoid material, (d)mixtures of synthetic cannabinoids or (e) a combination thereof;dissolved in one or more pharmaceutically and inhalation acceptablepropellant(s), optionally in the presence of one or morepharmaceutically and inhalation acceptable co-solvent(s) for thecannabinoid material(s); which formulation is delivered via a metereddose inhaler device without the need for heating over 50° C. duringdelivery and in the absence of heating over 50° C. during delivery. Forpurposes of this specification cannabinoid compounds are defined toinclude without limitation, those having any one of the structures I-IXbelow:

wherein R1 is lower alkyl, —CH₂(OH), —CH(OH)lower alkyl, —CHO,—C(═O)lower alkyl, or —COOH or a ester or amide or salt of —COOH or anester or salt of the alcoholic OHs, the complementary groups forming theesters and amides being pharmaceutically acceptable and preferably beinglower alkyl (for esters with acidic functions in the structures shown)and mono- di- and tri- lower alkylamines (for amides with acidicfunctions in the structures shown) and lower alkylcarbonyl (for hydroxyfunctions in the structures shown);R2 and R3 independently H, lower alkyl, or together are ═CH₂, or═CH-lower alkyl, or ═C (lower alkyl)(lower alkyl);R4 is H or lower alkyl;R5 and R6 are independently H or lower alkyl;and further with respect to Structural Formula VI that R4 and R5 mayalso together be CH₂═;R7-R10 are independently H, lower alkyl, —CH₂OH, —CHO, —COOH, or anester or amide or salt thereof, the group completing the ester or amideor salt being independently selected from the same moieties as describedabove:R11-R16 independently being H, or lower alkyl;all recitations of “alkyl” without specific carbon length or modified by“lower” being C1-C10 in length; and all recitations of “alkyl” and“lower alkyl” being understood as being straight chain or branchedchain. “Cannabinoid” compounds as used herein further includes each ofthe specifically named cannabinoids that are recited above or below.

Preferably the cannabinoid material is selected from any of the knowncannabinoids. These include, without limitation, tetrahydrocanabinols(includes without limitation Δ9 tetrahydrocannabinol and its isomers,especially, including without limitation, trans (−)-Δ9tetrahydrocannabinol, and trans (+)-Δ9 tetrahydrocannabinol) and theirisomers, tetrahydrocannabinolic acids (including without limitation Δ9tetrahydrocannabinolic acid, and its isomers, especially, includingwithout limitation, trans (−)-Δ9 tetrahydrocannabinolic acid, and trans(+)-Δ9 tetrahydrocannabinolic acid and their isomers) cannabidiol,cannabidiolic acid, cannabigerolic acid, cannabigerol,cannabigerovarinic acid, cannabigerolovarin, cannabichromenic acid,cannabichromene, cannabidivarin, cannabidivarinic acid, cannabivarin,cannabivarinic acid, tetrahydrocannabivarinic acid,tetrahydrocannabivarin, cannabinolic acid, cannabinol, cannabinodiol,cannabielsoin, cannabicyclol, and cannabicitran and isomers thereof, andvarious mixtures thereof. The foregoing cannabinoids further include thecorresponding acid variations of any of the specifically mentionednon-acid variants. Preferably the major component of a mixture ofcannabinoids is selected from one or more of Δ9 tetrahydrocannabinol, Δ9tetrahydrocannabinolic acid, cannabidiol, cannabidiol acid,cannabichromic acid, cannabichromene, cannabigerolic acid,cannabidivarin, cannabivarinic acid tetrahydrocannabivarinic acid,tetrahydrocannabivarin and cannabigerol, Even more preferably, thecannabinoid material is one or two cannabinoid pairs selected fromtetrahydrocannabinol (preferably a Δ9tetrahydrocannabinol)/tetrahydrocannabinolic acid (preferably a Δ9tetrahydrocannabinolic acid) and cannabidiol/cannabidiolic acid, whichmay have “very small amounts” of additional cannabinoids as well, the“very small amounts” being a weight/weight % of not greater than 20%(more preferably not greater than 10%, still more preferably not greaterthan 5%) relative to the total cannabinoid content of the formulation.When more than one major cannabinoid material is present, the totalmajor cannabinoid materials can be present at 80-100 wt/wt % of thetotal cannabinoid materials content of the formulation. In otherpreferred embodiments, the major cannabinoid materials are substantiallyall acid variant forms; in some even more preferable embodiments, all ofthe cannabinoid materials in the formulation are acid variant forms. Instill other embodiments, the major cannabinoids are CBD alone or withone or more cannabinoid acids. Unless, “cannabinoid acid” isspecifically being distinguished from “non-acid cannabinoid” in thisspecification, the term “cannabinoid” without the qualifier “acid” isdeemed to include both the cannabinoid acid forms and the cannabinoidnon acid forms.

The cannabinoid, whether extract, partially purified cannabinoid, orhighly purified cannabinoid or mixture thereof, can be dissolved ineither the pharmaceutically acceptable, inhalation acceptable propellantalone or first dissolved in a small amount of pharmaceuticallyacceptable, inhalation acceptable co-solvent. Where concentrations abovethe solubility of the cannabinoid components in the propellant aredesired, the co-solvent can be added to obtain higher concentrations ofthese materials without the use of heat above the temperatures indicatedelsewhere in this specification and in any event without the use ofheating the material beyond 50° C. or more preferably without heatingthe material beyond the more preferred temperatures specified below inthis paragraph. The pharmaceutically acceptable, inhalation acceptableco-solvent is selected from, without limitation, ethanol, propanol,propylene glycol, glycerol, polyethylene glycol (preferably withoutlimitation PEG 300 or PEG 400), or mixtures thereof, preferably selectedfrom ethanol, propanol, propylene glycol, glycerol, more preferablyethanol. When used, the co-solvent is present in an amount of from about0.05%, up to 30% based on the total of the propellant and co-solvent,more preferably, the co-solvent is present in ranges having a lowerlimit selected from 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%,0.2%, 0.25%, 0.30%, 0.35%, 0.40% 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.70%,075%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%,1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%,2.9%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, and 5.0%. an upperlimit selected from 0.5%, 0.55%, 0.6%, 0.65%, 0.70%, 075%, 0.8%, 0.85%,0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%,2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.25%,3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 10%, 15%, 20%, 25%, and 30%provided that the particular upper limit selected is greater than theparticular lower limit selected, each range being the amount ofco-solvent relative to the combination of co-solvent and propellant,each % being weight/weight %. In addition to being a co-solvent, theco-solvent may be suitably used to remove various insoluble contaminantsbefore adding the pharmaceutically acceptable, inhalation acceptablepropellant. In such situation, the cannabinoid material can be dissolvedin the co-solvent, and the solution is filtered to remove anynon-solubilized components and the filtered solution is then utilized.The filtration procedure can occur at room temperature or after coolingof the ethanol solution. If desired, mild heating can be used in thedissolution process, but is not to exceed a temperature selected from50° C., 45° C., 40° C., 35° C., and 30° C., preferably without raisingthe temperature above a temperature selected from 40° C., 35° C., and30° C., most preferably without the application of heat at all. (If itis desired to remove the particular co-solvent above after thefiltration, such removal can be done under the same conditions set forthbelow for the solvents that are not inhalation compatible.)Alternatively, if it is desired, for insoluble material removal, to usea solvent that is not acceptable for inhalation or is not compatiblewith the propellant, such solvent may be used to dissolve thecannabinoid material, filter out any non-solubles, and then remove theinhalation unacceptable solvent without the application of heat thatwould cause conversion of any of the present cannabinoids into anothercannabinoid. Thus, vacuum evaporation without any heating or withoutraising the temperature above a temperature selected from 50° C., 45°C., 40° C., 35° C., or 30° C., preferably without raising thetemperature above a temperature selected from 40° C., 35° C., or 30° C.,most preferably without the application of heat at all can be used.Suitable solvents that are not both inhalation acceptable andnon-interactive with the propellant for this “purification” aspect arelimited to those that can be removed suitably under these conditions.Such solvents that are either or both not inhalation acceptable and/orare incompatible with the propellant and suitable as per the abovelimitations include, but are not limited to, butane, pentane, hexanes,heptanes, diethyl ether, ethyl acetate, methylene chloride, chloroform,acetone and mixtures thereof is particularly preferred. Where mixturesof solvents are desired to be used for the rermoval of the insolubles,such mixtures can be of the “co-solvents”, mixtures of the“non-cosolvent solvents” or mixtures of both, provided that if anynon-cosolvent solvent is used, at least all of the non-cosolventsolvents must be removed before further formulation.

Propellants for the present invention are the pharmaceuticallyacceptable, inhalation acceptable hydrofluoroalkanes (HFAs). Theseinclude, but are not limited to, HFA 134a (tetrafluoroethane) HFA 227(heptafluoropropane) and mixtures thereof; HFA 134a and HFA 227 beingreadily available in the marketplace from Mexichem Fluor, Inc. Thepropellants comprise the bulk of the present formulations, typically inthe range of from 50% wt/wt to 99.5% wt/wt, preferably in the range from60% to 99%, more preferably in the range 80 to 99% and most preferablyin the range of 90% wt/wt to 99% wt/wt. Usually, the formulationcomprises the active materials, the propellant and optionally theco-solvent, preferably consists essentially of the active materials, thepropellant and optionally the co-solvent, still more preferably theformulation consists of the active materials, the propellant andoptionally the co-solvent.

For example, in the case of a 100 ul metered dose inhaler valve, thedelivered dose amount (from the metered dose inhaler unit) ofcannabinoid material present in the formulation is from 0.01 mg to 20 mgper 100 ul actuation of formulation (where the shot weight of theemitted volume (100 ul) of formulation would range from 80 mg to 140 mgdepending upon the presence of (and the particular) co-solvent and theparticular HFA used at 20° C. (for example using 100% HFA 227 and activeagent, the shot weight of 100 ul of formulation is about 140 mg).preferably in a range, per 100 ul of formulation, selected from thosehaving a lower limit selected from 0.01 mg, 0.02 mg, 0.025 mg, 0.03 mg,0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.075 mg, 0.08 mg, 0.09 mg, 0.1 mg,0.25 mg, 0.5 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg,1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.54 mg, 2.5 mg,2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg,3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.25 mg, 4.5 mg, 4.75mg, and 5.0 mg, and an upper limit selected from 1.0 mg, 1.5 mg, 1.6 mg,1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg,2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg,3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.25 mg, 4.5 mg, 4.75mg, 5.0 mg, 10 mg, 15 mg, and 20 mg provided that the selected upperlimit is greater than the selected lower limit. A highly preferredconcentration of the cannabinoid material in the formulation areselected from those above having a lower limit of at least 0.25 mg/100ul of formulation and an upper limit of not more than 10 mg/100 ul offormulation. Actual dosage is a function of the concentration of theactives in the formulation and the volume emitted by the device and therespirable fraction. Appropriate adjustments in the size (volume offormulation emitted) of the valve, concentration of active material inthe formulation, and respirable fraction (which can be varied with (a)the diameter of the stem block nozzle opening in the metered doseinhaler, (b) the amount of co-solvent in the formulation, (c) the valvemetering volume, all of which are well within the abilities of those ofordinary skill in the art having benefit of the present specification).For example, if the respirable fraction for a particular formulation istoo low (i.e., dosage reaching the lungs is not sufficient), it can beincreased by making the actuator orifice diameter opening smaller, orreducing the co-solvent concentration (if possible), or adjusting thevalve size to a smaller metering volume. If the respirable fraction istoo high, one can adjust these same parameters in the oppositedirection. Since these adjustments interplay with and affect oneanother, it is typical to construct a suitable device, test it forconsistency between manufacturing lots, determine the dose delivered bythe device, and determine the particle size of the emergent droplets andthe fraction of the dose reaching the lungs. Thereafter, one adjusts oneor more of the device or formulation parameters as mentioned above andre-determine the respirable dose being delivered to the lungs with themodified formulation/device. The process is repeated as needed untilsuch time as the precise formulation concentration, and deviceparameters are such that an appropriate actual dose (or suitablesurrogate therefor) is determined. Such testing as set forth herein,while not insignificant, is not undue experimentation, is well withinthe abilities of those of ordinary skill in the art having benefit ofthe present specification, and is generally required by regulatoryagency approval of the pharmaceutical product which includes both themetered dose inhaler package (canister, valve and actuator) and theformulation delivered thereby.

Non-limiting, typical properties of cannabinoids known in the art andinclude, without limitation, antibiotic, antifungal, antiinflammatory,analgesic, anxiolytic, antipsychotic, antioxidant, antispasmodic,antiemtic, sedative, anorectic, antidiabetic, antidepressant,antiepileptic, antiinsomnia, antiischemic, antiproliferative,antiosioratic, antipsychotic, anxiolitic, appetite stimulant, bonestimulant, anti-cancer, and the formulations of the present inventionmay be used to treat one or more thereof. Suitable dosings emitted fromthe inhaler used in the present CBD based formulations to deliveradequate therapeutic amounts would require a delivery of about 0.02 to20 mg of active principles about every 8 to 12 hours, which isconveniently obtained by a metered dose inhaler delivering about 0.01 to5 mg of active principles/spray with about 2-4 sprays per dose every8-12 hours provided the dose of active is suitably and efficiently (30%or more respirable fraction as determined by Cascade Impaction)delivered into the lungs. In other words, a total daily dose of theactive principles would be (0.02 to 20 mg per dosing)×(2-3 times aday)×(30% respirable fraction or more)=0.012 mg/day (based on a 30%respirable fraction and twice daily dosing) at the low end to 18 mg/day(based on a 30% respirable fraction and three times a day dosing) at thehigher end; 0.02 mg/day (based on a 50% respirable fraction and twicedaily dosing) at the low end to 30 mg/day (based on a 50% respirablefraction and three times a day dosing) at the high end, daily doses at atheoretical 100% respirable fractions being 0.04 mg/day to 60 mg/day.

Metered Dose inhalers of various design are generally available on themarket. However, not all available metered dose inhalers suitablydeliver the active substantially to the lungs, with a substantialportion being lost to the oral mucosa and the tongue. In situationswhere the first pass metabolism is not great, such a result may not playa significant role. However, in the present invention, substantiallosses to the oral mucosa will substantially affect the resultsachieved. Thus, it may be necessary to conduct a certain degree ofexperimentation with existing metered dose inhaler components orconstruct modifications thereof based on the results of suchexperimentation so as to meet target specific demands. The componentsreferred to are the formulation (as described above), the container, themetering valve, and the actuator device. A typical metered dose inhalerof the art is shown in FIG. 1. FIG. 1 illustrates a canister 100 used tocontain and aerosolize a liquid formulation 102 of the presentdisclosure. The canister 100 is received within a stem block cavity inan actuator 103, or inhaler. The liquid formulation 102 substantiallyfills a retaining cup 106 positioned in the valve of the canister 100. Apropellant 104 is used in the formulation by forming liquifiedpropellant, a major part of the liquid formulation 102. When thecanister 100 is pushed downward within the actuator 103, a meteringchamber 108, in the valve which contains a spring releases a precise,predetermined amount of the liquid formulation 102. The released liquidformulation 102 enters the expansion chamber 110 where the liquidformulation 102 is released and expands. The formulation 102 then exitsan actuator mouthpiece 112 forming an aerosolizing formulation 114. Theaerosolized formulation 114 is formed of droplets or particles measuringbetween one (1) and five (5) micrometers in diameter, for example, 2micrometers to 3 micrometers in diameter.

In use, a user can place their mouth over the exit of the actuator 103,press the canister 100 downward against the valve/actuator 103 andinhale deeply to carry the aerosolized formulation cloud 114 into thealveoli of the lungs, where active ingredients in the aerosolizedformulation 114 are deposited or absorbed rapidly into the blood stream,resulting in a faster perceived benefit of effect of the activeingredient while simultaneously bypassing first pass liver metabolismassociated with oral drug delivery.

The pharmaceutical solution formulations in hydrofluoroalkanes (HFAs)used in the present invention are filled into canisters suitable fordelivering pharmaceutical aerosol formulations. Canisters for use inmetered dose inhalers in the present invention generally comprisecontainers capable of withstanding the vapor pressure of the HFApropellant, such as plastic, or plastic coated glass bottles orpreferably a metal can, for example a stainless steel or aluminum canwhich is preferably anodized, organic coated and/or plastic coated.Generally suitable materials can be found in the disclosures ofWO/2015/195711, and WO/2015/200049, both of which are incorporated byreference with respect to suitable materials for metered dose inhalercomponents. In the event of a formulation incompatibility with aparticular container, one of the alternative containers above should betried, preferably plastic coated containers or anodized aluminum,stainless steel or glass. The container is sealed with a metering valve,the metering valve comprising a metering chamber is designed to delivera metered amount of the formulation per actuation and incorporates agasket to prevent leakage of propellant through the valve. The gasketmay comprise any suitable elastomeric material such as for example lowdensity polyethylene, chlorobutyl, black and white butadieneacrylonitrile rubbers, butyl rubber, and neoprene. A valve stem extendsfrom the metering valve and acts as a conduit to pass the metered doseinto a nozzle block situated in the actuator body in which the valvestem is inserted Suitable valves are commercially available frommanufacturers well known to the industry.

Each filled canister is fitted into a suitable channeled device(actuator) prior to use to form a metered dose inhaler package foradministration of the medicament into the lungs or nasal cavity,preferably into the lungs, of a patient. In a typical arrangement, thevalve stem is seated into a nozzle stem block which comprises anactuator orifice leading then to an expansion chamber/mouthpiece. Thisexpansion chamber/mouthpiece is how the patient interacts with theinhaler device to inhale the dose emitted upon actuation of the device.Conventional HFA actuators have variable actuator orifice diametersranging from 0.1 to 0.6 mm. The choice of actuator orifice size isdecided primarily by the formulation ingredients, the physicalproperties of the formulation and the lung or nasal target areas. Thegoal of this choice is to deliver highly respirable doses (at least 30%,preferably at least 35%, more preferable at least 40%, still morepreferable, at least 45%, most preferably at least 50%) capable ofreaching the lung (without significant losses to the actuator, valve,canister, the oral cavity, and by exhalation).

This selection effort requires significant testing of the deliverycharacteristics of the chosen package (actuator, valve, canister) withthe specific test formulation. While not all of these tests are relevantfor the determination of a suitable metered dose inhaler, many of thetests for product uniformity and reliability of the respirable fractionset forth in the United States Pharmacopeia (USP) 39, official from May1, 2016, Physical inhalation and Nasal Products, p. 423-449 Chapter onPhysical Tests and Determinations (incorporated herein by reference),are useful for the determination of whether a particular formulation inconjunction with a particular metered dose inhaler will meet thelimitations of the present invention. Once tested to obtain theparticular results of a particular formulation used with a particularmetered dose inhaler, those of ordinary skill in the art will be able toadjust active agent concentration, the concentration or presence of anyco-solvent, actuator design, and jet orifice diameter in order toachieve the appropriate combination of concentration, volume of deliveryof formulation per actuation, and respirable fraction so as to achievethe desired dosages as set forth herein. Where a single actuation isinsufficient to deliver the full dose target, multiple actuations can beused at a particular dosing point in order to achieve a suitable totaldose.

As stated above, the overall objective of the present invention is toachieve a therapeutically effective amount of active agent(s) to thelung with a minimal amount of losses to the oral cavity and metered doseinhaler components. This allows for the elimination of excessively largedoses that might otherwise be needed m order to achieve the desiredtherapeutically effective amount where losses to the oral cavity aresignificant (which may give rise to undesirable side effects). It shouldbe noted that the following tests are not limitations on the inventionbut are merely a convenience for testing product to determine whetherparticular devices and formulations when used in combination will resultin a method, combination (device with the formulation), or treatmentwithin the scope of one or more claims of the present invention.

Where the various in vitro tests are detailed in the USP (USP 39,chapter 601), those tests and testing equipment is the preferred methodof testing. It is recognized that the USP allows for a number ofvariations in the testing, but since the ultimate key result is arespirable fraction (for example at least 30%) of a particular amount ofactive agent reproducibly delivered by the metered dose inhalerutilizing a particular formulation is what is important, the precisemanner of obtaining these values is described in a validated test methoddeveloped for the specific product. The important aspect is that oneknows how much of the active agent mass is delivered out of the metereddose inhaler per actuation and what fraction of that amount is deliveredin a manner that is actually deposited in the lungs of a user. Sometests specified by the USP are for testing of product uniformity,metered dose inhaler to metered dose inhaler, some are for testingmetered dose inhaler consistency of delivered amount per actuation.These are performed to assure that the reliability of the metered doseinhaler unit used is properly working so that the remaining test resultscan be relied upon. Other tests are directed to determination of therespirable dose itself, which is important to the value of the presentinvention in reducing the amount of cannabinoid active agent needed tobe used per target dose to obtain a specific treatment effective amount.

The various tests one of ordinary skill in the art may use that are inthe USP or that are in addition to those in the USP, or that arealternatives to those in the USP but only after a correlation betweenthe USP test and the alternative has been appropriately validatedinclude, but are not limited to:

-   -   1. Spray actuation content uniformity thru the life of the unit        (beginning, middle and end stages of use) (testing reliability        of the metered dose inhaler unit being used). This test is        detailed in USP 39, chapter 601 and should be conducted in        accordance therewith.    -   2. Fine particle dose and fine particle fraction (respirable        fraction) thru the life of the unit by Cascade impaction        technologies (determination of the respirable fraction): This        test is detailed in USP 39, chapter 601 and should be conducted        in accordance therewith. At such time as a product of the        present invention is available on the market, samples of such        product should be tested in any specific protocol as a        confirmation that the specific protocol being used is valid by        resulting in the measured respirable fraction within the claim        limits of the present application and then such specific        protocol testing repeated with a proposed alternative product        when one wishes to determine if a proposed alternative product        is within the invention or not.

Once testing above is completed and the respirable fraction isdetermined, the dosage per actuation actually reaching the lung isestimated by multiplying the dose per actuation delivered (by themetered dose inhaler) by the respirable fraction. In cases where this istoo small for the desired dosing, one of ordinary skill adjustsconcentration of the active, the actuator design, the stem block jetorifice opening diameter or combination of one or more of the above andretests the modified formulation with the modified metered dose inhaler,or the original formulation with the modified metered dose inhaler orany combination thereof as appropriate. Based on those test results, theprocess may be repeated or not as desired until the various parametersare optimized to give a desired delivered dose of a formulation of thecannabinoid to the lungs of the subject being treated.

EXAMPLES

The following examples exemplify, but do not limit, the presentinvention.

Example 1

A formulation is prepared as set forth below.

CBD (98% pure powder)- 97 mg = 1.55% Ethanol-- 200 mg = 3.19%  HFA 134a5970 mg = 95.23%  Sub Total 6267 mg = 99.97    Impurities in CBD  2 mg =0.03% Total 6269 mg = 100.00%

The formulation is prepared as follows;

98% CBD powder (99 mg) is weighed out and transferred to a suitablecontainer and ethanol (0.2 g) added till solution is observed. Thesolution is transferred to an appropriate aerosol container (glass,aluminum) and a metered dose inhaler valve (100 ul) crimped on. Thesample is then pressure filled with 5.97 g HFA 134a. The final productis a yellow solution. This formulation will deliver about 2.0 mg of CBDper actuation.

Example 2

Following the procedure in example 1 except that the particularcomponents and amounts are selected as shown in the table below,formulations of the present invention are prepared:

Cosolvent Propellant Cannabinoid % w/w of % w/w of Example (98% CBD) gg/100 ul (ethanol)g formulation (HFA134a)g formulation 2a 0.0504 0.640.2 2.1 9.37 97.40 2b 0.0265 0.37 0.366 4.13 8.48 95.58 2c 0.098 0.0990.410 4.2 9.25 94.80

Example 3

Following the procedure in example 1 except that the particularcomponents and amounts are selected as shown in the table below and thestarting material is a 24% CBD enriched cannabinoid extract, aformulation of the present invention is prepared:

Cannabinoid Cosolvent Propellant (24% CBD) % w/w of % w/w of Example oilin g mg/100 ul (ethanol)g formulation (HFA134a)g formulation 1 0.51172.0 1.18 15.63 4.8 82.74

The formulation is prepared as follows;

Cannabinoid extract oil enriched in 24% CBD (0.5117 g of oil) is weighedout and transferred to a suitable container and ethanol (1.18 g) added.The resulting solution contained some insoluble particles which wereremove by filtration. It was determined that during filtration, 23% ofthe weight was lost. The filtered solution is transferred to anappropriate aerosol container (glass, aluminum) and a metered doseinhaler valve (100 ul) crimped on. The sample is then pressure filledwith 4.81 g HFA 134a. The final product is a yellow solution. Thisformulation would deliver 2.0 mg of CBD per actuation.

We claim:
 1. A cannabinoid component containing formulation comprising:(a) said cannabinoid component comprising one or more cannabinoid activeagent(s) (i) at least one of said one or more cannabinoid activeagent(s) is not selected from the group consisting oftetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),cannabidiol (CBD), cannabidiolic acid (CBDA) or salts thereof and (ii)optionally zero or one or more cannabinoids selected from the groupconsisting of tetrahydrocannabinol (THC), tetrahydrocannabinolic acid(THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), esters, amides,and salts thereof; (b) a hydrofluoroalkane (HFA) propellant; and (c) aco-solvent for said cannabinoid active agent, which co-solvent isethanol; said HFA propellant being present in an amount of from 50% byweight to 99.99% by weight based on the entire formulation; saidco-solvent, being present in an amount of from 0.1% by weight up to 40%by weight based on the entire formulation; and said cannabinoid activeagent being present, in an amount 0.01 mg/100 ul to 20 mg/100 ulrelative to the total formulation when only a single cannabinoid ispresent, and based on the total of the two most predominantly presentcannabinoid active agents present of 0.01 mg/100 ul to 20 mg/100 ul oftotal formulation, when more than one cannabinoid is present; whereinthe only active agents present in said formulation are (a) cannabinoidactive agents and (b) noncannabinoid active agents which noncannabinoidactive agents are otherwise naturally present in extracts of cannabinoidcontaining plant materials; and wherein glycerol is not present in saidformulation.
 2. The formulation of claim 1 wherein said cannabinoidcomponent is, subject to the limitations on cannabinoids of claim 1,selected from: (A) (i) an extract of a cannabinoid containing plantmaterial, said extract containing one or more first cannabinoid activeagent(s) or (ii) a combination of said extract and one or moreadditional cannabinoid active agent(s), said additional cannabinoidactive agent(s) selected from the group consisting of (a) partially orcompletely purified cannabinoid compounds, (b) synthetic cannabinoidcompounds, and (c) mixtures thereof; or (iii) an active containingmaterial selected from the group consisting of (a) an extract of acannabinoid containing plant material, said extract containing one ormore first cannabinoid active agent(s), (b) partially or completelypurified second cannabinoid active agents, (c)synthetic secondcannabinoid active agents, and (d) mixtures thereof; wherein said firstcannabinoid active agent(s) of (A)(iii) and said second cannabinoidactive agent(s) of (A)(iii) being independently selected from the groupconsisting of: (a) Formula I and/or Formula IIa (i) wherein R1 is—CH2(OH), —CH(OH)lower alkyl, —CHO, or —C(═O)lower alkyl, or apharmaceutically acceptable ester of any alcoholic OHs; R2 and R3 areindependently H, lower alkyl, or together are ═CH2, or ═CH-lower alkyl,or ═C-(lower alkyl)(lower alkyl); R4 is H or lower alkyl; R5 and R6 areindependently H or lower alkyl; R7-R8 are independently H, lower alkyl,—CH2OH, —CHO, —COOH, or a pharmaceutically acceptable ester orpharmaceutically acceptable amide or a pharmaceutically acceptable saltthereof; (ii) wherein R1 is lower alkyl, —CH2(OH), —CH(OH)lower alkyl,—CHO, —C(═O)lower alkyl, or —COOH or a pharmaceutically acceptable esteror a pharmaceutically acceptable amide or a pharmaceutically acceptablesalt of said —COOH or a pharmaceutically acceptable ester of anyalcoholic OHs; at least one of R2 and R3 are independently H, ortogether are ═CH2, or ═CH-lower alkyl, or ═C-(lower alkyl)(lower alkyl);R4 is H or lower alkyl; R5 and R6 are independently H or lower alkyl;R7-R8 are independently H, lower alkyl, —CH2OH, —CHO, —COOH, or apharmaceutically acceptable ester or pharmaceutically acceptable amideor a pharmaceutically acceptable salt thereof; (iii) wherein R1 is loweralkyl, —CH2(OH), —CH(OH)lower alkyl, —CHO, —C(═O )lower alkyl, or —COOHor a pharmaceutically acceptable ester or a pharmaceutically acceptableamide or a pharmaceutically acceptable salt of said —COOH or apharmaceutically acceptable ester of any alcoholic OHs; R2 and R3 areindependently H, lower alkyl, or together are ═CH2, or ═CH-lower alkyl,or ═C-(lower alkyl)(lower alkyl); R4 is lower alkyl; R5 and R6 areindependently H or lower alkyl; R7-R8 are independently H, lower alkyl,—CH2OH, —CHO, —COOH, or a pharmaceutically acceptable ester orpharmaceutically acceptable amide or a pharmaceutically acceptable saltthereof; (iv) wherein R1 is lower alkyl, —CH2(OH), —CH(OH)lower alkyl,—CHO, —C(═O)-lower alkyl, or —COOH or a pharmaceutically acceptableester or a pharmaceutically acceptable amide or a pharmaceuticallyacceptable salt of said —COOH or a pharmaceutically acceptable ester ofany alcoholic OHs: R2 and R3 are independently H, lower alkyl, ortogether are ═CH2, or ═CH-lower alkyl, or ═C-(lower alkyl)(lower alkyl);R4 is H or lower alkyl; at least one of R5 and R6 is lower alkyl; R7-8are independently H, lower alkyl, —CH2OH, —CHO, —COOH, or apharmaceutically acceptable ester or pharmaceutically acceptable amideor a pharmaceutically acceptable salt thereof; (v) wherein R1 is loweralkyl, —CH2(OH), —CH(OH)lower alkyl, —CHO, —C(═O)lower alkyl, or —COOHor a pharmaceutically acceptable ester or a pharmaceutically acceptableamide or a pharmaceutically acceptable salt of said —COOH or apharmaceutically acceptable ester or pharmaceutically acceptable salt ofany alcoholic OHs; R2 and R3 are independently H, lower alkyl, ortogether are ═CH2, or ═CH-lower alkyl, or ═C-(lower alkyl)(lower alkyl);R4 is H or lower alkyl: R5 and R6 are independently H or lower alkyl; atleast one of R7-R8 is lower alkyl, —CH2OH, or —CHO, and the other ofR7-R8is lower alkyl, —CH2OH, —CHO, or —COOH, or a pharmaceuticallyacceptable ester or pharmaceutically acceptable amide or apharmaceutically acceptable salt thereof; and (vi) compounds of FormulaIa wherein R1 is lower alkyl, —CH2(OH), —CH(OH)lower alkyl, —CHO,—C(═O)lower alkyl, or —COOH or a pharmaceutically acceptable ester or apharmaceutically acceptable amide or a pharmaceutically acceptable saltof said —COOH or a pharmaceutically acceptable ester of any alcoholicOHs; R2 and R3 are independently H, lower alkyl, or together are ═CH2,or ═CH-lower alkyl, or ═C-(lower alkyl)(lower alkyl); R4 is H or loweralkyl; R5 and R6 are independently H or lower alkyl; R7-R8 areindependently H, lower alkyl, —CH2OH, —CHO, —COOH, or a pharmaceuticallyacceptable ester or pharmaceutically acceptable amide; wherein allrecitations of “alkyl” without specific carbon length or modified by“lower” being C1-C10 in length; and all recitations of “alkyl” and“lower alkyl” being understood as being straight chain or branchedchain; and (b) formulae III-IX further Formula IIb and mono-, di, andtri- saturations at ring positions 1-6 of Formula IIb other thancompounds of Formula IIa wherein R1 is lower alkyl, —CH2(OH),—CH(OH)lower alkyl, —CHO, —C(═O)-lower alkyl, or —COOH or apharmaceutically acceptable ester or a pharmaceutically acceptable amideor a pharmaceutically acceptable salt of said —COOH or apharmaceutically acceptable ester of any alcoholic OHs; R2 and R3 areindependently H, lower alkyl, or together are ═CH2, or ═CH-lower alkyl,or ═C-(lower alkyl)(lower alkyl); R4 is H or lower alkyl; R5 and R6 areindependently H or lower alkyl; and with respect to Formula VI, R4 andR5 may together also form CH2=; R7-R10 are independently H, lower alkyl,—CH2OH, —CHO, —COOH, or a pharmaceutically acceptable ester orpharmaceutically acceptable amide or a pharmaceutically acceptable saltthereof; R11-R16 independently being H, or lower alkyl; wherein allrecitations of “alkyl” without specific carbon length or modified by“lower” being C1-C10 in length; and all recitations of “alkyl” and“lower alkyl” being understood as being straight chain or branchedchain; and (c)tetrahydrocannabinol (THC), a tetrahydrocannabinolic acid(THC Acid), cannabidiol (CBD), cannabidiolic acid (CBD Acid),cannabigerolic acid, cannabigerol, cannabigerovarinic acid,cannabigerolovarin, cannabichromenic acid, cannabichromene,cannabidivarin, cannabidivarinic acid, tetrahydrocannabivarinic acid,tetrahydrocannabivarin, cannabivarinic acid, cannabivarin, cannabinolicacid, cannabinol, isomers thereof, and mixtures thereof; and (d)mixtures thereof; (B) a hydrofluoroalkane (HFA) propellant; and (C) aco-solvent selected from the group consisting of ethanol; said HFApropellant being present in an amount of from 50% by weight to 99.99% byweight based on the entire formulation; said co-solvent, being presentin an amount of from 0.1% by weight up to 40% by weight based on theentire formulation; and said extract (A)(i) or said combination of saidextract and said additional cannabinoid active agent(s)(A)(ii) or saidactive containing material (A)(iii) being present, in an amount based onthe total of the two most predominantly present cannabinoid activeagents of from 0.01 mg/100 ul to 20 mg/100 ul of total formulation;wherein said extract (A)(i) and A(ii) contains from 1 up to 5 majorcannabinoid pairs, each major cannabinoid pair consisting of the Acidand non-Acid forms thereof, wherein to be considered a major cannabinoidpair, the cannabinoid pair must be at least 20% of the total cannabinoidcontent of the formulation, wherein said extract(A)(i), (A)(ii), and(A)(ii)(a) is each obtained in the absence of applying heat at all or inthe absence of applying heat greater than 50° wherein Formulae I-IX are:


3. The formulation of claim 2 comprising: cannabinoid materialcomprising at least one cannabinoid active agent, said cannabinoidmaterial being an extract of a cannabinoid containing plant material; ahydrofluoroalkane (HFA) propellant; and a co-solvent for saidcannabinoid active agent which is ethanol; said HFA propellant beingpresent in an amount of from 50% by weight to 99.99% by weight based onthe entire formulation; said co-solvent, being present in an amount of0.1% by weight up to 21.05% by weight based on the entire formulation;and said cannabinoid material being present, in an amount based on thetotal of the two most predominantly present cannabinoid active agents of0.01 mg/100 ul to 13.3 mg/100 ul of total formulation; wherein saidextract contains from 1 up to 5 major cannabinoid pairs, each majorcannabinoid pair consisting of the acid and non-acid forms thereof,wherein to be considered a major cannabinoid pair, the cannabinoid pairmust be at least 20% of the total cannabinoid content of theformulation, said major cannabinoid pairs being present collectively inan amount greater than 80% of the cannabinoids present in said extract,wherein each of said major cannabinoid pairs is present substantially inthe acid from thereof; and wherein said extract is obtained in theabsence of applying heat at all or in the absence of applying heatgreater than 50° C.
 4. The formulation of claim 2 wherein component (A)is selected from (A)(i) and (a)(ii).
 5. The formulation of claim 2wherein the co-solvent is present in an amount of from 0.1% by weight to15% by weight based on the entire formulation.
 6. The formulation ofclaim 2 wherein the propellant is selected from HFA 134a and HFA
 227. 7.The formulation of claim 1 wherein said at least one cannabinoid isselected from the group consisting of cannabigerolic acid, cannabigerol,cannabigerovarinic acid, cannabigerolovarin, cannabichromenic acid,cannabichromene, cannabidivarin, cannabidivarinic acid,tetrahydrocannabivarinic acid, tetrahydrocannabivarin, cannabivarinieacid, cannabivarin, cannabinolic acid, cannainabinol, isomers thereof,and mixtures thereof; and said optionally zero or one or morecannabinoids is selected from the group consisting oftetrahydrocannabinol (THC), a tetrahydrocannabinolic acid (THC acid),cannabidiol (CBD), cannabidiolic acid (CBD acid), cannabigerolic acid,cannabigerol, cannabigerovarinic acid, cannabigerolovarin,cannabichromenic acid, cannabichromene, cannabidivarin, cannabidivarinicacid, tetrahydrocannabivarinic acid, tetrahydrocannabivarin,cannabivarinic acid, cannabivarin, cannabinolic acid, cannabinol,isomers thereof, and mixtures thereof.
 8. The formulation of claim 1,wherein cannabidiol and cannabidiolic acid are present among the topfive most predominantly present cannabinoid materials in saidformulation.
 9. A cannabinoid component containing formulationconsisting of: (a) said cannabinoid component consisting of (I) one ormore cannabinoid active agent(s) (i) at least one of said one or morecannabinoid active agent(s) is not selected from the group consisting oftetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),cannabidiol (CBD), cannabidiolic acid (CBDA) or salts thereof and (ii)optionally zero or one or more cannabinoids selected from the groupconsisting of tetrahydrocannabinol (THC), tetrahydrocannabinolic acid(THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), esters, amides,and salts thereof; (II) optionally non-cannabinoid active agents andinactive agents, each of said non-cannabinoid active agents and inactiveagents being selected from the group consisting of those naturally foundin extracts of cannabinoid containing plant materials; (b) ahydrofluoroalkane (HFA) propellant; and (c) a co-solvent for saidcannabinoid active agent, which co-solvent is selected from the groupconsisting of ethanol; said HFA propellant being present in an amount offrom 50% by weight to 99.99% by weight based on the entire formulation;said co-solvent, being present in an amount of from 0.1% by weight up to40% by weight based on the entire formulation; and said cannabinoidactive agent being present, in an amount 0.01 mg/100 ul to 20 mg/100 ulrelative to the total formulation when only a single cannabinoid ispresent, and based on the total of the two most predominantly presentcannabinoid active agents present of 0.01 mg/100 ul to 20 mg/100 ul oftotal formulation, when more than one cannabinoid is present; whereinglycerol is not present in said formulation.
 10. A formulation of claim1 comprising: (A) from 1 to 5 major cannabinoid active agents, whereeach of said major cannabinoid active agent is required to be present inan amount of at least 20% of the total cannabinoid content of saidformulation, each of said major cannabinoid active agents being selectedfrom the group consisting of (a) partially or completely purifiedcannabinoid compounds, (b) synthetic cannabinoid compounds, and (c)mixtures thereof, and each of said major cannabinoid active agents beingsubstantially in the acid form thereof; (B) optionally, one or morenon-major cannabinoid active agents being present in individual amountsrelative to the total cannabinoid content of said formulation of notmore than 20% and collectively being present in an amount based on thetotal cannabinoid content of said formulation of not more than 20%,where said non-major cannabinoid active agents may be present as theiracid forms, their non-acid forms, or mixtures thereof, and when presentin mixtures of said acid form and said non-acid form, the above 20%maximum limitation applies to the total of each pair of acid form andnon-acid form of otherwise the same cannabinoid; (B) a hydrofluoroalkane(HFA) propellant; and (C) a co-solvent for said cannabinoid activeagent(s), said co-solvent selected from the group consisting of ethanol;said HFA propellant being present in an amount of from 50% by weight to99.99% by weight based on the entire formulation; said co-solvent, beingpresent in an amount of from 0.1% by weight up to 40% by weight based onthe entire formulation; and said cannabinoid active agent(s) beingpresent, in an amount based on the total of the two most predominantlypresent cannabinoid active agents of from 0.01 mg/100 ul to 20 mg/100 ulof total formulation.
 11. The formulation of claim 10 wherein theco-solvent is present in an amount of from 0.1% by weight to 15% byweight based on the entire formulation.
 12. The formulation of claim 10wherein the propellant is selected from HFA 134a and HFA 227 andmixtures thereof.
 13. The formulation of claim 10 wherein the majorcannabinoid active agent(s) are independently selected from the groupconsisting of tetrahydrocannabinolic acid (THC acid), cannabidiolic acid(CBD acid), cannabigerolic acid, cannabigerovarinic acid,cannabichromenic acid, cannabidivarinic acid tetrahydrocannabivarinicacid, cannabivarinic acid, cannabinolic acid, isomers of the foregoing,and mixtures thereof.
 14. The formulation of claim 13 wherein said CBDacid and/or said THC acid is present among the top five mostpredominantly present cannabinoid active agents in said formulation. 15.A method of administration of a cannabinoid material while substantiallyavoiding first-pass metabolism thereof associated with oraladministrations and avoiding heat associated chemical alteration of oneor more of the active agent components of said formulation comprisingadministering the formulation of claim 1 via a metered dose inhalationdelivery system in the absence of any heating or with heating to notmore than 40° C.
 16. The method of administration of claim 15 whereinsaid delivery system using said formulation delivers an amount based onthe total of the two most predominantly present cannabinoid activeagents of from 0.01 mg/100 ul to 20 mg/100 ul of total formulation in ashot weight with a respirable fraction of at least 30%w/w relative toactive agent contained in the shot weight.
 17. A method of treating acannabinoid responsive condition comprising delivering a cannabinoidmaterial via the method of administration of claim
 15. 18. A method ofproviding an effective therapeutic effect of at least two cannabinoidacids from a formulation containing said cannabinoid acids andoptionally one or more additional cannabinoid active agents comprisingadministering said cannabinoid acids, optionally together with said oneor more other cannabinoid active agents via the method of claim 15, at alower total daily dose of the total cannabinoid content of saidformulation relative to the total cannabinoid daily dose needed toobtain the same effective therapeutic effect via each of an oralingestion, sublingual administration, smoking, vaporizing, and topicaladministration in which the same cannabinoid and cannabinoid acidprofile and relative amounts as in said formulation are employed. 19.The method of claim 18 wherein said method provides said effectivetherapeutic effect at a lower total dose than administration of the samecannabinoid profile as in said formulation via each of oral ingestion,smoking, or vaporized inhalation administration.
 20. A method oftreating a cannabinoid acid responsive condition while substantiallyavoiding or substantially reducing psychotropic effects of cannabinoidnon-acid forms comprising administering at least one cannabinoid acidcompound, optionally together with another cannabinoid acid in aformulation of claim 1 via a metered dose inhaler system wherein saidformulation is administered in a therapeutically effective amount forsaid cannabinoid acid responsive condition wherein said effective amountof said cannabinoid acid is substantially reduced compared to thetherapeutically effective amount for the same cannabinoid acidresponsive condition when being treated by oral ingestion, smoked,vaporized inhalation delivery, or topical administration of saidcannabinoid acids, alone or optionally with said additional cannabinoidrespectively.
 21. A formulation of cannabinoid agents of claim 1comprising: (A) at least a major cannabinoid component, said majorcannabinoid component comprising (i) at least a first cannabinoid activeagent; and (ii) at least a second cannabinoid active agent, which is forany particular formulation different than the cannabinoid present assaid first cannabinoid active agent; and (iii) optionally 1-3 furthercannabinoid active agents; each of said first and second cannabinoidactive agents and said optional further cannabinoid active agents beingfreely selected from known natural or synthetic cannabinoid agents andeach being substantially in the acid form thereof; said first and secondand said optional further cannabinoid active agents individuallycomprising at least 20% based on the acid form thereof relative to thetotal cannabinoid content of the formulation, and said first, second andsaid optional further cannabinoid active agents collectively comprisingbased on the acid-forms thereof at least 80% of the total cannabinoidcontent of said formulation; (B) optionally up to 20% of the totalformulation cannabinoid content of one or more additional cannabinoidsnot already part of a particular formulation under said majorcannabinoid active agents, which said additional cannabinoids may bepresent in the acid form or non-Acid form or combination thereof (C) anHFA propellant 50% to 99.99% by wt based on the entire formulation (D)aco-solvent in an amount of 0.1% up to 40% by weight based on the entireformulation selected from ethanol; the active material being present inan amount based on the total of the two most predominantly presentcannabinoid active agents of 0.01 mg/100 ul to 20 mg/100 ul of totalformulation.